Invasive fungal infections in paediatric patients treated with macromolecular immunomodulators other than tumour necrosis alpha inhibitors

Abstract

An expanding list of immunomodulatory or immunosuppressive monoclonal antibodies (mAbs) and biologic therapeutics is currently entering clinical practice, particularly in the areas of oncology, transplantation and autoimmune disorders. These agents are directed against molecules or cells involved in inflammation and immunity and may therefore be associated with serious and opportunistic infections. The purpose of this review was to critically analyse the literature on invasive fungal infections (IFIs) occurring in association with mAbs and fusion proteins other than tumour necrosis alpha (TNF-α) inhibitors, including therapeutics modulating T-cell-mediated pathologies (muromonab, abatacept, belatacept, ipilimumab, basiliximab, daclizumab), inducing lymphopenia (alemtuzumab), depleting CD20+ B cells (rituximab) and interfering with various targets (anakinra, natalizumab, blodalumab, ixekizumab and others) with a focus on children, and to provide a framework of evaluating the risk for IFIs in this population.

Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies

“…Muromonab-CD3 (Orthoclone OKT3 ® , Ortho-Biotech Products, LP, Bridgewater, NJ, USA) was the first mAb ever to be approved (back in 1985) but is no longer being marketed due to decreased demand and increased infection rates, especially as regards IFDs and in particular invasive aspergillosis. Muromonab targeted CD3, a T-cell co-receptor involved in the activation of both cytotoxic CD8+ naïve Tcells and CD4+ T-helper naïve cells, explaining the detrimental impact of T-cell depletion on IFD occurrence [4].…”

“…However, assessing the exact contribution to infection rates in children with hematologic malignancies receiving biologic therapies is problematic, as many of them are more or less immunocompromised by default and thus at greater risk of infection. Preceding and concomitant immunosuppressive therapies usually render us uncapable of defining the exact relative risk for IFDs conferred by each drug [4]. Host defenses against fungi rely on the sophisticated interplay between: (i) mucocutaneous barrier integrity; (ii) cells of the innate immune system (e.g., dendritic cells and macrophages) that recognize specific pathogenassociated molecular patterns (PAMPs) and bind fungal cell walls using pattern recognition receptors (PRRs) like C-type lectin receptors (CLRs, e.g., dectin-1 recognizing β-glucan, mannose receptor, melanin sensing C-type Lectin receptor MelLec and CARD9 mediator) and Toll-like receptors (TLRs, e.g., TLR2); (iii) cell-mediated immunity via transduction of signals from RPRs and associated molecules (FcRγ, recognition of chitin by the intracellular receptors TLR9 and NOD2) and by phagocytosis, initiation of killing mechanisms (e.g., production of reactive oxygen species), and development of adaptive immunity-especially by CD4+ T-cells producing IFNγ (Th1) or IL-17 (Th17) that attract innate effector cells such as neutrophils and macrophages [5,6].…”

Fungal Diseases in the 21st Century: The Near and Far Horizons

“…For the near horizon, it is likely that the current trends of an increasing prevalence of fungal diseases will continue. Considering that modern medicine is in the midst of a revolution in antibody-based immunotherapies that target specific immune molecules and cells, we can anticipate an increasing number of individuals at risk for invasive fungal diseases [ 14 ]. For example, the introduction of revolutionary tumor necrosis blockage therapy for rheumatologic diseases created a new type of host susceptible to fungal diseases [ 15 ].…”

Treatment of severe psoriasis with ixekizumab in a liver transplant recipient with concomitant hepatitis B virus infection

“…After discussing potential therapeutic strategies for psoriasis with the patient, it was decided to opt for treatment with ixekizumab, in agreement with the consultant infectivologist. Since candidiasis has been reported with increasing frequency in patients treated with anti-interleukin 17 inhibitors (Kyriakidis, Tragiannidis, Zündorf, & Groll, 2017), it should be noted that the patient did not develop candidiasis during the clinical follow-up, or any other infection.…”

“…Since candidiasis has been reported with increasing frequency in patients treated with anti‐interleukin 17 inhibitors (Kyriakidis, Tragiannidis, Zündorf, & Groll, ), it should be noted that the patient did not develop candidiasis during the clinical follow‐up, or any other infection.…”